Endothelial cells (EC) in the heart play a variety of important roles both during development and in the adult animal. Cardiac EC are uniquely poised to act as sensors of systemic stress (by virtue of exposure to circulating factors) as well as sensors and regulators of cardiac stress and function (by virtue of their close proximity to cardiac myocytes). The idea that cardiac EC play a critical role in autocrine/paracrine regulation of the adult heart is supported by the finding that removal of either of these types of EC has been shown to have significant detrimental effects on the contractile function of the adjacent cardiac myocytes, though the factors mediating this effect are incompletely defined. Our global hypothesis is that neuregulin (NRG) is one such factor. NRG has been shown to potentially play 2 very important roles in the cardiovascular system: 1) protection of cardiac myocytes; and 2) promotion of endothelial cell proliferation and angiogenesis. These effects could play a crucial role in preventing cardiovascular injury. We and others have shown that EC release NRG in response to cytokines or ischemia. Our focused aims in this proposal are to test whether NRG released by EC in the setting of ischemia protects the heart by 1) preventing EC and myocyte apoptosis, 2) promoting angiogenesis, and 3) increasing myocyte glucose uptake. We will test these aims using complimentary models of in vitro hypoxia/reoxygenation, and intact heart and in vivo models of ischemia/reperfusion. This novel approach will integrate both molecular signaling effects and metabolic effects of NRG in the clinically relevant setting of ischemia and give us insight into potential targets for therapeutic manipulation of this important signaling pathway in the cardiovascular system.